This invention relates to an implantable device including polyamino acid(s), wherein the polyamino acid(s) can form a coating or film on the device or the device itself can be formed from polyamino acid(s).
Stenosis is a narrowing or constriction of a duct or canal. A variety of disease processes, such as atherosclerotic lesions, immunological reactions, congential abnormalities, and the like, can lead to stenosis of arteries or ducts. In the case of stenosis of a coronary artery, this typically leads to myocardial ischema. Percutaneous transluminal coronary angioplasty (PTCA), i.e., the insertion and inflation of a balloon catheter into a stenotic vessel to affect its repair, is widely accepted as an option in the treatment of obstructive coronary artery disease. Other vascular invasive therapies include antherectomy (mechanical systems to remove plaque residing inside an artery), laser ablative therapy, and the like. However, restenosis at the site of a prior invasive coronary artery disease therapy occurs in a majority of cases. Restenosis, defined angiographically, is the recurrence of a 50% or greater narrowing of a luminal diameter at the site of a prior coronary artery disease therapy, such as a balloon dilatation in the case of PTCA therapy. Restenosis is a major problem that limits the long-term efficacy of invasive coronary disease therapies. In particular, an intra-luminal component of restenosis develops near the end of the healing process initiated by vascular injury, which then contributes to the narrowing of the luminal diameter. This phenomenon is sometimes referred to as xe2x80x9cintimal hyperplasia.xe2x80x9d In some instances, restenosis develops so rapidly that it may be considered a form of accelerated atherosclerosis induced by injury. Additionally, the rapid onset of restenosis is compounded by the lack of predictability to determine which patients, vessels, or lesions will undergo restenosis.
Although the mechanism of restenosis is not fully understood, clinical evidence suggests that restenosis results from a migration and rapid proliferation of a subset of predominately medially derived smooth muscle cells, which is apparently induced by the injury caused by the invasive therapy. Such injury, for example, is caused by the angioplasty procedure when the balloon catheter is inflated and exerts pressure against the artery wall, resulting in medial tearing. It is known that smooth muscle cells proliferate in response to mechanical stretch and stimulation by a variety of growth factors. It is believed that such proliferation stops one to two months after the initial invasive therapy procedure but that these cells continue to express an extracellular matrix of collagen, elastin, and proteoglycans. Additionally, animal studies have shown that after balloon injury, denudation of endothelial cells occurs, followed by platelet adhesion and aggregation, and the release of platelet-derived growth factor (PDGF) as well as other growth factors. As mentioned above, this mass of tissue contributes in the re-narrowing of the vascular lumen in patients who have restenosis. It is believed that a variety of biologic factors are involved in restenosis, such as the extent of the injury, platelets, inflammatory cells, growth factors, cytokines, endothelial cells, smooth muscle cells, and extracellular matrix production, to name a few.
Attempts to inhibit or diminish restenosis include administration of pharmacological agents, such as aspirin, antiplatelet drugs, anticoagulants, corticosteroids, calcium-channel blocker, fish oils, and the like, all of which have demonstrated limited success. Other solutions include providing a stent coated with an anti-thrombogenic agent that may reduce platelet and fibrin deposition (U.S. Pat. No. 4,768,507 to Fischell et al.) or providing a stent including fibrin and an elutable drug capable of providing treatment of restenosis (U.S. Pat. No. 5,591,227 to Dinh et al.). Still other methods to diminish restenosis include the delivery of modified viruses, especially adenoviruses, that carry gene sequences capable of ameliorating or preventing the symptoms of cardiovascular disease, such as that described in International Publication No. WO 94/27612 (French et al.).
In searching for alternative therapies that may decrease the likelihood of restenosis, gamma radiation has been shown to limit cell proliferation by arresting cell division thereby reducing the number of clonal progenitors. However, re-injury or other stimuli can induce a response by smooth muscle cells by migration, proliferation and matrix synthesis, as mentioned above. Ionizing radiation has been shown to inhibit thymidine uptake and collagen synthesis by cultured fibroblasts. For example, it has been shown that low doses of superficial x-rays after surgery may prevent hypertrophic scarring and keloid formation that typically results from the excessive formation of collagen after surgical injury. Thus, radiation may inhibit cellular hyperplasia by either killing progenitor cells or limiting their replication.
What is yet needed is an implantable device capable of reducing the occurrence of restenosis, for example by reducing inflammation, with or without delivering therapeutic drugs to the in vivo treatment site.
This invention relates to an implantable device capable of reducing restenosis. Preferably, the implantable device according to the invention is biodegradable once implanted in a body lumen to treat or prevent injury. The term xe2x80x9cinjuryxe2x80x9d means a trauma, which may be incidental to surgery or other treatment methods including deployment of a stent, or a biologic disease, such as an immune response or cell proliferation caused by the administration of growth factors. In addition, the methods of the invention may be performed in anticipation of xe2x80x9cinjuryxe2x80x9d as a prophylactic. A prophylactic treatment is one that is provided in advance of any symptom of injury in order to prevent injury, prevent progression of injury or attenuate any subsequent onset of a symptom of such injury.
In accordance with the invention, an implantable device includes a structure including a polyamino acid component. The polyamino acid component includes L-arginine, and preferably consists essentially of two different amino acids, one of which is L-arginine. The polyamino acid component may form a film or a coating on at least a portion of the structure or the polyamino acid component may form an integral portion of the structure.
In another embodiment, the polyamino acid component of the structure includes a mixture of polyamino acids. The mixture, which may be a polymer blend, includes at least one polyamino acid that includes, and preferably consists essentially of, L-arginine and one other amino acid, and at least one polyamino acid that includes, and preferably consists essentially of, two amino acids other than L-arginine.
The structure of the device preferably includes a shape which is capable of minimizing restenosis in an internal human body site, such as an artery, vein, urethra, other body lumens, cavities, and the like. In one embodiment, the shape is preferably generally cylindrical, and more preferably, the shape is selected from the group of a catheter, a stent, and a guide wire. In another embodiment, the shape is preferably generally sheet-like.